Taking a big step

It was not what David Hackam, MD’92, had planned, but thanks to the influence of a famed London surgeon early in his career, he now stands on the brink of helping more children than he ever imagined possible.

“I wanted to be a paediatrician and neonatologist. I wanted to help children,” Hackam said. “But then I rotated with this new recruit to London – Murray Girotti, a hot-shot trauma surgeon, an engaging teacher and an amazing human being.”

It proved a pivotal encounter. Girotti, the former Chief of Surgery at Victoria Hospital and a Schulich School of Medicine & Dentistry professor, “set the stage” for Hackam to become the esteemed surgeon-scientist who today sits at the helm of the Johns Hopkins Children’s Center in Baltimore as co-director and paediatric surgeon-in-chief.

“Murray had this following,” Hackam continued. “I quickly became one of them. I just wanted to be around him. He went out of his way to engage me and make me feel like I was a valued member of the team.”

Yet, when Girotti approached him about becoming a surgeon, Hackam begged off at first, resolute in pursuing paediatrics. However, his next few rotations brought a change of heart.

“They were boring. There was no excitement, no pace, you weren’t really fixing things the way you do in surgery. I still had this nagging feeling I wanted to be a paediatrician, but now I wanted to be a surgeon. I thought, ‘How is this possible? How could I join these two worlds?’”

The answer was paediatric surgery, a relatively new field at the time. And when it came time to pursue his training in the area, Girotti once again held sway and directed Hackam “to the mecca, SickKids in Toronto.”

At the Hospital for Sick Children, Hackam conducted fundamental research, taking a three-year hiatus from his residency to earn his doctorate in cell biology. “I knew doing things the way we’d always done them was not going to make a difference on society or children’s health,” he explained. “There were diseases we needed to investigate.”

Among those in need of exploration was necrotizing enterocolitis – or NEC – a ravaging disease that causes the sudden death of parts of the intestine in premature babies.

“These children are sitting in the NICU, humming along, and out of the blue, they start to get sick,” he said. “Their belly gets swollen, and then, within 24 hours, they’re either dying or dead. When you operate on these kids, you see that their intestines have gone from pink and happy to violent and black. It’s devastating for these families.”

Hackam remembers “little Freddie,” a premature newborn he met as a newly minted attending surgeon at a community hospital in Pittsburgh. Freddie’s parents were somewhat older and became close to Hackam – and vice versa. All stood witness to the short, difficult life of the little boy. Despite numerous operations, Freddie died about one month shy of his first birthday.

“It was at that point, through that journey with that family, I decided to devote my research career to NEC,” Hackam said.

His quest has led to ground-breaking discoveries and established him as a leading authority on intestinal inflammation and bowel disease in infants. Notably, his team has shown that a protein known as TLR4 is behind the malfunction that fuels necrotizing enterocolitis.

TLR4 is required for the normal development of the intestine, and once the gut is made, its expression in the intestine goes away. When a premature baby’s still-developing intestines enter the world and become colonized with bacteria, the immature TLR4 protein is still present in the tiny, underdeveloped gut. It then goes haywire, shutting off the oxygen supply to the gut cells, which causes the rapid death of intestinal tissue.

To combat the effects of TLR4, Hackam’s lab has also shown that sodium nitrate – a substance found in breast milk – can block TLR4 and stave off necrotizing enterocolitis in preemies by increasing the oxygen supply to the gut. By adding that substance to infant formula, researchers can prevent necrotizing enterocolitis in premature animal models. They have also identified novel agents present in breast milk that directly inhibit TLR4, and which can be engineered to synthetic formulas to mimic the effects of breast milk and thus prevent NEC.

As that research continues with an eye toward the future, there are cases happening every day. Currently, NEC is treated by intestinal transplants or feeding tubes. Neither option is ideal.

“If you lose all your intestine, you still need to eat,” Hackam explained. “Your brain is fine; your legs are fine; you just need fuel. The only treatment is intestinal transplant. But it’s not ideal. There aren’t intestines available for every child and the incidence of mortality is still quite high.”

The better solution is an artificial intestine made from the patient’s own intestinal tissue. Hackam’s team has grown the lining of an intestine in a dish by harnessing the rapid and regenerative nature of stem cells.

It was a big step. But what was missing, was a tubular surface – or scaffold – the stem cells could grow upon. John March, a biomedical engineer from Cornell University, created such a thing. And he showed up at the right time, right place – a bar, actually – while in town attending the same scientific conference as Hackam.

“It was a total geek encounter. I was talking about how I wanted to make an artificial intestine – because that’s what you talk about at a bar,” Hackam laughed. “I said, ‘I can make these stem cells I take from the intestine grow. I can do it in mice and other animals. I just wish I had something to grow them on that looked like an intestine.’ Next to me at the bar was John (yes, that's his real name). He had this scaffold and had shaped this platform in a way that looked just like a real intestine.

“We started talking. I said, ‘You’ve got a scaffold and need stem cells; I’ve got stem cells and I need a scaffold. We should get together.”

They did. The two teams collaborated to create an artificial gut, with their model being the first to successfully recreate the delicate finger-like projections of the intestine, called microvilli, integral to absorbing nutrients.

“We take stem cells at the time of surgery, and grow them in a dish. Then we take a customized scaffold that’s the right size and shape of the patient. We place the cells on the scaffold, which grow in this tube. It is then implanted into the mouse in an organ called the omentum that gives it a blood supply. Then we hook it up with whatever intestine is left, and – assuming this will work in humans as well as it works in mice – now the patient has a new intestine made from their own stem cells,” Hackam said.

They’ve found great success in small-to-mid-size animal models and predict human trials are hopefully only three to five years away.

“We’ve got a little way to go. But we feel like we’re a little bit like the Wright Brothers,” Hackam said. “We’re tinkering now; we have a concept; we think we can make this thing fly. Now, we’re optimizing the conditions, to make it really soar.

“And when it does, we believe we can offer new hope to these tiny patients, which is our ultimate goal.”

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